Diagnostic accuracy of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil–lymphocyte-to-platelet ratio biomarkers in predicting bacteremia and sepsis in immunosuppressive patients with cancer: literature review

Abstract Background: This literature review explores the role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil–lymphocyte-to-platelet ratio (NLPR) biomarkers, as potential indicators for predicting bacteremia and sepsis in patients with cancer. Objective: Tracing the evolution of interest in this area since 2001, the aim of this review was to report a comprehensive overview of current knowledge and gaps, particularly in patients undergoing immunosuppression. Summary of Findings: The literature research indicates the potential of NLR, PLR, and other biomarkers in diagnosing and predicting sepsis, with some studies emphasizing their value in mortality prediction. A specific focus on bacteremia shows the effectiveness of NLR and PLR as early indicators and prognostic tools, though mostly in noncancer patient populations. While NLR and PLR are promising in general cancer patient populations, the review addresses the challenges in applying these biomarkers to patients with neutropenic and lymphopenic cancer. The NLPR could be considered a significant biomarker for inflammation and mortality risk in various medical conditions, yet its diagnostic accuracy in patients with immunosuppressed cancer is not extensively validated. Conclusion: This review offers a snapshot of the current research on biomarkers in patients with immunocompromised cancer in the sepsis and bacteremia area. More focused research on their application is necessary. This gap underscores an opportunity for future studies to enhance diagnostic and prognostic capabilities in this high-risk group.


Introduction
The role of biomarkers as predictors of bacteremia and sepsis has been the subject of several studies in the last two decades.Neutrophil-lymphocyte ratio (NLR) is calculated as the neutrophil count divided by the lymphocyte count, associated with the imbalance between neutrophils and lymphocytes in the proinflammatory and anti-inflammatory response (Fig. 1).This ratio has been considered an important biomarker predictor of cancer prognosis, for the occurrence of sepsis, and the decision of the therapeutical regimen. 1,22][3][4][5][6][7][8] On the other hand, the neutrophil-lymphocyte-to-platelet ratio (NLPR) is increasingly used as an accuracy parameter to assess the degree of inflammation.Both biomarkers are frequently associated with a poorer prognosis and elevated mortality rates in critically ill patients.3][14] In cases where sepsis is suspected, a blood culture test remains the gold standard for confirming bacteremia. 15However, the sensitivity and specificity of the blood culture testing may be influenced by several variables, including the timing of specimen collection, the volume of blood sampled, prior antibiotic use, the presence of fastidious or slow-growing organisms, adequacy of culture media, and the incubation period of the culture. 16Consequently, the reliability of blood culture tests in accurately detecting the presence or absence of infection may be compromised, increasing the risk of false-negative or false-positive results, potentially leading to incorrect or delayed diagnoses and inappropriate treatments. 13 the context of bacteremia and sepsis, there is growing attention on studies investigating blood culture assessment and the types of microorganisms involved. 158][19] Therefore, the aim of this review was to focus on the state-of-the-art diagnostic accuracy of NLR, PLR, and NLPR in predicting bacteremia and sepsis in immunosuppressed cancer patients.

Results/Discussion
There is an increasing interest in the relationship between hematological biomarkers and various medical conditions, particularly in oncology and infectious diseases, aiming to elucidate their diagnostic and prognostic significance comprehensively.This discussion is structured into five subchapters, each focusing on a specific aspect of this complex interplay.This structured approach not only facilitates a systematic exploration of the topics but also underscores the multifaceted roles of NLR, PLR, and NLPR across different medical disciplines (Table 1).Chapter 1: variability in neutrophil, lymphocyte, and platelet ratios: the impact of hematological disorders and oncological therapies In the context of cancer, NLR and PLR have emerged as significant biomarkers of cancer-related details and valid prognostic indicators, particularly for solid tumors. 30,31] On the other hand, low values below 0.7 are associated with morbidity and mortality in critically ill septic patients.20  The NLR can be used for cancer stratification, correlating with tumor size, stage, metastatic potential, and lymphatic invasion.Furthermore, it plays an independent prognostic role in cancerfree survival and is valuable for monitoring oncological therapy outcomes.Elevated PLR is negatively associated with overall survival and serves as a predictive marker for neoadjuvant chemotherapy effectiveness in solid tumors.NLPR is increasingly recognized as a significant biomarker in various fields such as COVID-19, identification of causative pathogens, multiple myeloma, small-cell lung cancer, and burn patients, particularly for prognosis and risk assessment.22 Hematology disorders significantly impact blood studies, but solid tumors may also induce a systemic inflammatory response that may release cytokines and growth factors stimulating neutrophil production in the bone marrow.7,34,35 Hematological disorders exhibit nondiscriminatory prevalence across diverse conditions.The bone marrow could be affected and disrupted with normal blood cell production in various clinical scenarios, affecting individuals regardless of their health status, age, gender, or other demographic factors.36 Immunocompromised patients undergoing chemotherapy and radiation treatments may experience a decrease in neutrophils, platelets, or lymphocytes compromising host immune response and increasing susceptibility to bacterial infections.37 Systematic inflammatory responses, lymphocytopenia, and thrombocytosis interact with neutrophilia in varying levels of these ratios.Moreover, cancer treatments may induce severe neutropenia, lymphocytopenia, and thrombocytopenia, further affecting these ratios.

Chapter 2: biomarkers in sepsis and bacteremia: enhancing diagnostic accuracy and prognostic prediction
The literature has several studies focusing on the diagnosis and prediction of sepsis and bacteremia, offering diverse perspectives, particularly in noncancer patient populations.Gurol et al 33 (2015) identified an NLR $5 as a potential marker for bacterial infection.Ljungstr öm et al 22 (2017) reported that combining biomarkers (PCT, NLR, CRP) improve the diagnostic accuracy for bacterial sepsis, regardless of using Sepsis-2 or Sepsis-3 criteria.Expanding on the temporal aspects, Kaushik et al 23 (2018) noted that elevated NLR levels are observed in the early phase of sepsis, aiding diagnosis, while late-phase values serve as prognostic indicators.Further supporting the prognostic value of NLR, Shi et al 31 (2019) found that a day 5 NLPR and NLR were independently correlated with in-hospital mortality.
Shen et al 30 (2019) studied PLR as a prognostic predictor of mortality in sepsis, involving 5537 patients with sepsis, of varied underlying conditions, and observed that PLR values at admission were associated with increased mortality risk.Complementing these findings, Yoldas et al (2020) evaluated NLR and PLR as markers for predicting hospital stay and mortality in intensive care settings, with a focus on noncancer patients.They found that the median NLR was 2.06 (range: 1.18-21.68)for survivors and 10.42 (range: 2.85-48.20)for deceased patients.Similarly, the median PLR in the deceased group was significantly higher than that in the survivor group [268.9 (range: 150-3000) and 55.7 (range: 11.8-152.5),respectively].These markers, along with C-reactive protein levels, were identified as predictors of mortality in critically ill adult patients. 38uilding on this approach to enhance diagnostic sensitivity, Spoto et al 39 (2021) studied the association between clinical signs and biomarkers to increase diagnostic sensitivity of sepsis and predict disease severity and mortality, finding that NLR and PLR are associated with 90-day mortality in patients with sepsis.Lorente et al 24 (2022) evaluate the association between NLR in the first seven days of sepsis and mortality, controlling for sepsis severity.In addition, Botos et al 32 (2023) identified day 14 of NLR, low peripheral blood-derived NLR (dNLR), and PLR as independent predictors of septic shock and mortality in patients with sepsis.

Chapter 3: evaluating NLR and PLR as predictive tools in bacteremia conditions
The exploration of biomarkers, in patients with bacteremia and blood culture testing, provides valuable insights applicable across diverse clinical contexts.
Terradas et al 25 (2012) conducted a retrospective analysis focusing on patients experiencing their first episode of community-acquired or healthcare-related bacteremia during hospital admission.This approach allowed for the examination of eosinophil count and NLR in a specific clinical context, revealing their prognostic value.This study excluded patients with hematological malignancies and identified sustained eosinopenia and NLR .7 as independent markers of mortality in patients with bacteremia.Expanding on this concept, Lowsby et al 40 (2015) studied NLR as an early indicator of bloodstream infection in the emergency department, suggesting its potential for guiding the clinical management of suspected bacteremia cases.Similarly, Loonen et al (2014) and Laukemann et al (2015)  studied clinical scores incorporating biomarkers and biomarker levels to predict bacteremia and reduce unnecessary blood cultures, with NLR providing effectively for sepsis prediction. 26,41hifting focus to a broader patient population, Salciccioli et al 42 (2015) studied 5056 critically ill adult patients, revealing that an elevated NLR at ICU admission is associated with higher 28-day mortality, particularly in nonseptic patients.The study suggests that NLR may be a useful indicator of inflammatory response and prognosis in critical illness but highlights the need for more research to fully understand these associations.Hwang et al 20 (2016) conducted a retrospective cohort study with 1395 emergency department patients, categorizing them by initial NLR values and identifying persistent low or high NLR as significant risk factors for 28-day mortality, particularly highlighting the potential utility of NLR among patients with cancer for management of septic complications.
Taking a prognostic perspective, Zhang et al 27 (2016) studied NLR according to blood culture test results, excluding patients with hematological malignancies and bone marrow infiltrations, and found high diagnostic efficiency of NLR predicting sepsis.Similarly, Djorjdjevic et al 28 (2018) studied a prospective cohort of 392 critically ill adult and injured patients, observing NLR and PLR with different blood cultures and concluding NLR as an independent predictor of mortality.Focusing on platelet count as a biomarker, Sinha et al 43 (2021) studied a critically ill population of 130 adult patients, analyzing NLR, PLR, and mean corpuscular volume (MCV) with 28-day hospital mortality and length of stay outcomes.The study identified thrombocytopenia on day 1 and decreased eosinophil count on day 3 as predictors of 28-day mortality in patients with sepsis.

Chapter 4: advancing diagnostic precision: biomarker efficacy in bacteremia and sepsis beyond cancer contexts
Moving from broader cancer-related studies to specific research, Jager et al 17 (2010) conducted an insightful investigation into the diagnostic capabilities of lymphocytopenia and NLR in bacteremia.This study evaluated the effectiveness of these biomarkers compared with conventional biomarkers in predicting bacteremia among patients presenting to the emergency department with positive blood cultures.The study population included 184 patients (92 patients with confirmed bacteremia and a control group of 92 patients without bacteremia).Notably, patients with hematological diseases, those receiving chemotherapy and those on glucocorticoids, were excluded.The results showed that lymphocytopenia and NLR are superior predictors of bacteremia compared with traditional markers, such as C-reactive protein and white blood cell count.NLR, in particular, exhibited higher sensitivity and specificity, highlighting its potential as a diagnostic tool in emergency Building upon these findings, Naess et al 18 (2017) conducted a study focusing on the roles of NLR and monocyte-to-lymphocyte ratio (MLR) in patients with fever of unknown origin.The study involved 299 patients and analyzed NLR and MLR with final diagnostic groups and fever duration.Higher NLR and MLR values were associated with a higher probability of bacterial infection and a lower probability of viral infection.The study included a subset of 26 patients with compromised immune systems, primarily transplant recipients and patients with HIV, excluding patients with leukemia due to the potential impacts on white blood cell counts.
From an alternative perspective, Qiu et al 19 (2024) conducted a retrospective analysis of 172 sepsis patients with lymphopenia to assess the prognostic value of NLR and PLR.The study identified cutoff values of 18.93 for NLR and 377.50 for PLR in predicting hospital mortality.Higher NLR and PLR values were found to be independent predictors of mortality, providing valuable insights for clinical decision making in sepsis management.
Chapter 5: emerging research and future directions of cytopenic hematological biomarkers in patients with cancer: insights and unmet needs NLR and PLR have emerged as significant prognostic indicators in recent studies, due to their accessibility and quantification.In 2020, Joshua Farkas proposed that NLR and the fraction of immune granulocytes warrant further investigations as emergency indicators. 7Similarly, a prospective study by Kim et al 44 (2019) emphasized the importance of PLR following granulocyte colonystimulating factor (G-CSF) administration in patients with septic shock.This study found that PLR combined with the APACHE II score, independently predicts one-month survival in these patients.
Zahorec 2 (2021) in the review "Neutrophil-to-Lymphocyte Ratio: Past, Present, and Future," highlighted the extensive use of NLR to evaluate inflammatory responses and immune system activation across various medical conditions, including cancer.During the COVID pandemic, a retrospective study led by Yang et al 29 (2022) in China emphasized the predictive role of NLR in cancer patients with sepsis.Key variables such as NLR, brain natriuretic peptide (BNP), fluid accumulation, and the Sequential Organ Failure Assessment (SOFA) score were identified as independent risk factors of 28-day mortality.A developed nomogram incorporating these factors demonstrated good predictive accuracy.Up to this date, based on our current knowledge, this article is one of a few studies conducted in a cancer facility.Therefore, the gap in the literature for immunosuppressive patients becomes evident when considering the NLR's role in typical oncological settings.Comprehensive reviews by Buonacera et al 8 (2022) and Firment et al 1 (2024) highlighted the applicability and effectiveness of the NLR and the Zahorec index (a biomarker derived by the ratio between neutrophil count and lymphocyte count) across various clinical conditions, including sepsis, cancer, and postsurgical responses.The review by Buonacera et al 8 (2022) explores how chronic inflammation contributes to tumorigenesis and cancer progression, emphasizing NLR's significance as a biomarker for ongoing cancer-related inflammation, and NLR correlates with tumor size, stage, metastatic potential, and lymphatic invasion, making it a valuable tool for stratifying patients with cancer and predicting outcomes.While hematological biomarkers have demonstrated utility in standard cancer patient populations, gaps exist regarding their application in patients with neutropenic and lymphopenic cancer which requires further investigation in typical oncology settings.

The dual nature of current biomarker research: successes and limitations
There are some gaps in the scientific research.First, there is a notable lack of focus on immunocompromised patients with cancer.Despite this limitation, several studies provide valuable insights into the general applicability of NLR, PLR, and NLPR as biomarkers, setting a foundation for future research specifically tailored to immunocompromised patients.Second, studies often face potential confounding factors of diverse natures.Highlighting these potential confounders is crucial for guiding future research to control for these variables, thereby enhancing the understanding of biomarkers in specific patient populations.Third, caution is needed in generalization findings.A cautious approach to generalization underscores the need for more specific research, compelling the scientific community to address these gaps.
Conversely, there has been a marked and successful surge in interest in this field, providing a snapshot of the current state of research and identifying trends and gaps crucial for guiding future research directions.

Conclusion
In conclusion, while the literature review demonstrates the utility of hematological biomarkers in standard cancer patient populations, particularly in predicting mortality outcomes, it does not specifically address their application in patients with neutropenic and lymphopenic cancer.This emphasized the need for more dedicated studies in this domain.

a
Oncology Clinical Research Unit IPO Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto.CCC) & RISE@CI-IPOP (Health Research Network), Porto, Portugal, b Oncology Nursing Research Unit IPO Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto.CCC) & RISE@CI-IPOP (Health Research Network), Porto, Portugal, c Approach to Precursor Lesions and Early Cancer Research Unit IPO Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto.CCC) & RISE@CI-IPOP (Health Research Network), Porto, Portugal, d Public Health Department and Forensic Sciences and Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal, e Molecular Oncology and Viral Pathology Group Research Unit IPO Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto.CCC) & RISE@CI-IPOP (Health Research Network), Porto, Portugal

Figure 1 .
Figure 1.Imbalance between the pro-inflammatory and the anti-inflammatory response, neutrophils/lymphocytes.

Figure 2 .
Figure 2. Imbalance between coagulation and immune system response.

Table 1
Multifaceted roles of NLR, PLR, and NLPR across different medical disciplines: a representative selection of the literature review.